Post-translational Regulation of Radioactive Iodine Therapy Response in Papillary Thyroid Carcinoma

Background: Radioactive iodine (RAI) is the mainstay of treatment for differentiated thyroid carcinoma (DTC). Nevertheless, the mechanism of RAI resistance that occurs in many patients with DTC remains unknown. We aimed to elucidate the role of post-translational regulation of radioiodine uptake. Methods: We analyzed the expression pattern of the ribosomal glycosylphosphatidylinositol transamidase (GPIT) complex in freshly excised tumors from 10 patients with DTC. We used functional RAI uptake assays to assess the role of GPIT in iodine uptake both in vivo and in vitro. The effects of MEK inhibition on the GPIT subunit PIGU and the sodium iodide symporter (NIS) were assessed in three DTC cell lines and in four human DTC biopsies. We used a multivariable logistic regression model to study the role of PIGU in the response to RAI treatment in advanced DTC. All statistical tests were two-sided. Results: Expression profiling of different GPIT complex subunits revealed statistically significantly lower expression of PIGU in papillary carcinomas than in matched normal thyroid tissue (P < .001). Expression of PIGU in the K1 human papillary carcinoma cell line resulted in a robust increase in NIS glycosylation and trafficking to the cell membrane, accompanied by a robust increase in I-125 uptake both in vitro (465 200 +/- 56 343 vs 1236 +/- 156 counts per million, P < .001) and in vivo (128 945 +/- 28 556 vs 7963 +/- 192 counts per million, P < .001, n = 5 mice per group). Treatment with the MEK inhibitors U0126 and PD302 rescued PIGU expression. Finally, the PIGU expression levels in tumors of 18 patients with recurrent DTC were associated with a biochemical response to RAI treatment (hazard ratio = 8.06, 95% confidence interval = 3.72 to 12.3, P = .001). Conclusions: We showed that downregulation of PIGU in DTC determines NIS function and RAI avidity. This represents a novel mechanism for RAI resistance.